Cancer cells contain a genetically unstable chromosome and hold a tendency to evolve in response to drug challenges. See Lengauer et al., Nature, 396, 643-649 (1998); and Orth et al., Proc. Natl. Acad. Sci. U.S.A., 91, 9495-9499 (1994). Patients treated with a single agent often develop resistance even if showing an initial response. The use of a combination of multiple drugs (i.e., “combinational chemotherapy”) can offer the potential benefit of simultaneously inhibiting several anti-cancer targets and therefore preventing or delaying the emergence of drug resistance. See LoRusso et al., Clin. Cancer Res., 18, 6101-6109 (2012). Combinational chemotherapy has been adopted as the first-line treatment of many advanced cancers. See Saltz et al., J. Clin. Oncol., 26, 2013-2019 (2008); Maughan et al., Lancet, 377, 2103-2114 (2011); Giacchetti et al., J. Clin. Oncol., 18, 136 (2000); Hurwitz et al., J. Clin. Oncol., 23, 3502-3508 (2005). However, the difference in solubility, potency, pharmacokinetics and bioavailability among drugs can make the dose schedule for combinatorial chemotherapy challenging. See Duan et al., ACS Nano, 7, 5858-5869 (2013); Lehar et al., Nat. Biotechnol., 27, 659-666 (2009); and Tai et al., Mol. Pharm., 7, 543-556 (2010). Moreover, simple noncovalent encapsulation of multiple agents into a single particle can lead to untunable drug composition and uncontrollable and/or premature release of drug.
Accordingly, there is still an ongoing need in the art for additional drug delivery agents, such as agents to deliver multiple drugs for combinational chemotherapy. More particularly, there is an ongoing need for multi-drug delivery agents that are easy to prepare in large scale manufacturing, that can provide a tunable drug loading ratio to provide a precise dose schedule, that can have stealth properties to decrease macrophage clearance and avoid immune system attack, and/or that have high drug loading capacity.